chr13-23354978-C-A

Variant names:

• chr13-23354978-C-A
• rs1555254281
• NM_014363.6:c.1634G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001437336.1(SACS):​c.1634G>T​(p.Trp545Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SACS NM_001437336.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.83
• Publications: 0 publications found

Genes affected

SACS (HGNC:10519): (sacsin molecular chaperone) This gene encodes the sacsin protein, which includes a UbL domain at the N-terminus, a DnaJ domain, and a HEPN domain at the C-terminus. The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. This gene includes a very large exon spanning more than 12.8 kb. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. The authors of a publication on the effects of siRNA-mediated sacsin knockdown concluded that sacsin protects against mutant ataxin-1 and suggest that "the large multi-domain sacsin protein is able to recruit Hsp70 chaperone action and has the potential to regulate the effects of other ataxia proteins" (Parfitt et al., PubMed: 19208651). A pseudogene associated with this gene is located on chromosome 11. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

SACS Gene-Disease associations (from GenCC):

• Charlevoix-Saguenay spastic ataxia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001437336.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	NM_014363.6	MANE Select	c.1634G>T	p.Trp545Leu	missense	Exon 8 of 10	NP_055178.3
	SACS	NM_001437336.1		c.1634G>T	p.Trp545Leu	missense	Exon 8 of 11	NP_001424265.1
	SACS	NM_001278055.2		c.1193G>T	p.Trp398Leu	missense	Exon 6 of 8	NP_001264984.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	ENST00000382292.9	TSL:5 MANE Select	c.1634G>T	p.Trp545Leu	missense	Exon 8 of 10	ENSP00000371729.3
	SACS	ENST00000455470.6	TSL:1	c.1634G>T	p.Trp545Leu	missense	Exon 8 of 11	ENSP00000406565.2
	SACS	ENST00000402364.1	TSL:2	c.-617G>T		5_prime_UTR_premature_start_codon_gain	Exon 6 of 8	ENSP00000385844.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.79	P
Vest4		0.91
MutPred		0.78		Gain of catalytic residue at K540 (P = 0.0101)
MVP		0.54
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.70
gMVP		0.73
Mutation Taster		=173/127	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555254281; hg19: chr13-23929117;